Linkage Screen for BMD Phenotypes in Male and Female COP and DA Rat Strains

Abstract

ABSTRACT:Because particular inbred strains of experimental animals are informative for only a subset of the genes underlying variability in BMD, we undertook a genome screen to identify quantitative trait loci (QTLs) in 828 F 2 progeny (405 males and 423 females) derived from the Copenhagen 2331 (COP) and dark agouti (DA) strains of rats. This screen was performed to complement our study in female Fischer 344 (F344) and Lewis (LEW) rats and to further delineate the factors underlying the complex genetic architecture of BMD in the rat model. Microsatellite genotyping was performed using markers at an average density of 20 cM. BMD was measured by pQCT and DXA. These data were analyzed in the R/qtl software to detect QTLs acting in both sexes as well as those having sex-specific effects. A QTL was detected in both sexes on chromosome 18 for midfemur volumetric BMD (vBMD; genome-wide, p < 0.01). On distal chromosome 1, a QTL was found for femur and vertebral aBMD as well as distal femur vBMD, and this QTL appears distinct from the proximal chromosome 1 QTL impacting BMD in our F344/LEW cross. Additional aBMD and vBMD QTLs and several sex-specific QTLs were also detected. These included a male-specific QTL (p < 0.01) on chromosome 8 and a female-specific QTL on chromosomes 7 and 14 (p < 0.01). Few of the QTLs identified showed overlap with the significant QTLs from the F344/LEW cross. These results confirm that the genetic influence on BMD in the rat model is quite complex and would seem to be influenced by a number of different genes, some of which have sex-specific effects.

Uncovering the liver’s role in immunity through RNA co-expression networks

“…The bone mineral density phenotypes Bmd51 and Bmd52 are associated with the variability in femur areal and volumetric bone mineral density, respectively (Koller et al 2008). …”

Genes influencing spinal bone mineral density in inbred F344, LEW, COP, and DA rats

“…As described previously, lumbar phenotypes were obtained from 595 female F2 offspring derived from F344 and LEW progenitors and 423 female F2 offspring derived from COP and DA progenitors (Koller et al 2005, 2008). At 26 weeks of age, the rats were euthanized, and lumbar vertebrae (L3–L5) were dissected out for densitometry analysis.…”

“…At 26 weeks of age, the rats were euthanized, and lumbar vertebrae (L3–L5) were dissected out for densitometry analysis. Total vBMD (milligram per cubic centimeter) of the L5 were measured using a Norland Stratec XCT Research SA + pQCT machine as described previously (Koller et al 2005, 2008). Genomic DNA was isolated from the rat spleen; genotyping was accomplished using microsatellite markers, and quantitative linkage analysis of L5 vBMD was performed as described previously (Koller et al 2005, 2008).…”

“…We also demonstrated that despite similar body size, substantial variation exists in bone geometry and biomechanical properties among adult Fischer 344 (F344), Lewis (LEW), Copenhagen 2331 (COP), Dark Agouti (DA) rats (Turner et al 2001). Subsequently, we have generated a large number of second filial (F2) female progeny derived from (F344 × LEW) and (COP × DA) crosses and detected QTLs influencing lumbar volumetric BMD (vBMD) (Koller et al 2005, 2008). The QTLs with strongest linkage for spinal vBMD were detected within the regions of chromosomes (Chrs) 10 (q12–q31) and 15 (p16–q21) in F344 × LEW and COP × DA crosses, respectively.…”

“…The purpose of this study was to narrow the list of candidate genes within these QTL regions contributing to the variation in spinal vBMD among F344, LEW, COP, and DA rats. We chose these rats because, at present, they are the only available rat models in which bone QTLs have been identified (Koller et al 2005, 2008). In addition, we selected female rats for this study because our initial QTL analysis in F344 and LEW study (Koller et al 2005) was done only in female rats; whereas, we included both male and female rats for QTL analysis in COP and DA study (Koller et al 2008).…”